Antimicrobial compounds are defined as molecules that can inhibit or stop the growth of micro-organisms or kill them. In this context, they are commonly used to prevent or treat human and animal infections, and in the agrifood industry to prevent multiplication of pathogenic bacteria in food. Widespread use of antimicrobial compounds favors the emergence of resistant infectious agents. The spread of bacteria that has acquired resistance mechanisms for the most widely used antimicrobial compounds is a more and more alarming major public health problem (J. S. Bradley et al. Lancet Infect. Dis. 2007; 7:68-78).
As an illustration, many strains resistant to antibiotics for the most pathogenic species of genus Staphylococcus, i.e. Staphylococcus aureus, have been isolated. Staphylococcus infections represent a high percentage of serious infections. What is more, almost half of nosocomial infections are reportedly related to staphylococcus. Mention may be made of the many strains of Enterococcus faecalis or Enterococcus faecium that are resistant to commonly used antibiotics. Although they are less virulent than staphylococci in particular, an increasing number of multiresistant enterococcus strains and more recently epidemics of enterococci resistant to glycopeptides, the antibiotics of recourse for this bacterial family, have been identified.
Another antibioresistance phenomenon has been described that might not only be related to the excessive use of antibiotics, but to food storage methods. So for example it has been shown that Listeria monocytogenes is more resistant to antibiotics after having undergone osmotic stress, at a low temperature or in an acidic medium (Anas A. et al. (2015) Food Microbiology, Volume 46, April, Pages 154-160). That is, the human contamination comes from food. In addition, although it is relatively rare, human listeriosis is a serious infection with mortality estimated at 50%. Accordingly, the emergence of antibiotic resistance in L. monocytogenes that could be caused by modern storage or treatment methods for food constitutes a serious threat to public health.
Although several mechanisms are often involved simultaneously in antibiotic resistance, it is common to classify it into three categories: (a) lack of antibiotic penetration into the bacterium, (b) inactivation or excretion of the antibiotic by bacterial enzymatic systems and (c) lack of affinity between the bacterial target and the antibiotic. These three resistance mechanism categories have a structural component, i.e. the mechanisms used are dependent on the structure of the molecule concerned.
No process in the prior art can produce an isomeric mixture of biosourced compounds with low toxicity and low cost.
Nevertheless, biosourced compounds have been described. Accordingly, different compounds used as antimicrobials have been described, among which are fatty acids and their corresponding polyhydroxylated esters that are active against Gram-positive bacteria and having long aliphatic chains. As an indication, one of the most active antimicrobials is monolaurine, a glycerol monoester with a C12 aliphatic chain. Its trade name is LAURICIDIN®. This compound is used as a food additive to inhibit bacterial growth (E. Freese, C. W. Sheu, E. Galliers. Nature 1973, 241, 321-325; E. G. A. Verhaegh, D. L. Marshall, D.-H. Oh. Int. J. Food Microbiol. 1996, 29, 403-410). The ester function of the monolaurine is sensitive to esterases, so this compound degrades quickly and has a short half-life.
Also described are antimicrobials derived from sugar considered as particularly attractive because of their biodegradability, their low toxicity and environmental impact.
Examples of antimicrobials derived from sugar are the esters derived from sugar that are also used industrially for antimicrobial applications because their raw materials and production costs remain relatively low. Mention may be made for example of sorbitan caprylate described in international patent application WO2014/025413 in mixture with Hinokitiol in an antimicrobial formulation. According to this application, this formulation will inhibit or kill Gram-positive and negative bacteria, fungi and/or yeast.
Also described is the use of disaccharide esters as antimicrobial agents in the food industry. Dodecanoyl sucrose is one of the most used. It is reportedly particularly active against L. monocytogenes (M. Ferrer, J. Soliveri, F. J. Plou, N. López-Cortés, D. Reyes-Duarte, M. Christensen, J. L. Copa-Patiño, A. Ballesteros, Enz. Microb. Tech., 2005, 36, 391-398). Nevertheless, it is also described as weakly inhibiting the growth of S. aureus, for hospital applications (J. D. Monk, L. R. Beuchat, A. K. Hathcox, J. Appl. Microbiol., 1996, 81, 7-18). It reports that the sucrose ester presents properties that are bacteriostatic (stops bacterial growth) but not bactericidal (kills the bacteria).
In addition, the synthesis of sugar esters presents many drawbacks. First, in spite of the low production cost, synthesizing esters, more particularly for di- and trisaccharides, is problematic because of sugars' high functionality, which causes the formation of a mixture of mono-, di- and polyesters and the presence of a polar solvent, such as dimethylformamide (DMF) and pyridine, is generally necessary to better solubilize the highly polar reagents. However, these solvents are classed as carcinogenic, mutagenic and reprotoxic (CMR) and their use must be avoided. To solve this problem, enzymatic synthesis was used but the need to use very dilute media in these conditions makes production limited.
Moreover, the ester functions on these compounds are easy for the esterases present in the cells to hydrolyze. The molecules released after this hydrolysis, i.e. the sugar and the fatty acid, have little or no antimicrobial properties (the fatty acid is slightly active). This causes instability that is responsible for reduced activity in these compounds.